Adjuvant chemotherapy in pancreatic cancer at different AJCC stages: a propensity score matching analysis

Objective In the treatment of resectable pancreatic cancer, adjuvant chemotherapy is viewed as essential. However, it is yet unclear how well adjuvant chemotherapy works at different illness stages. This study aims to investigate the efficacy of adjuvant chemotherapy in various pancreatic cancer stages. Materials and methods Patients with pancreatic cancer who underwent surgical intervention at Sun Yat-sen University Cancer Center between January 2018 and January 2021 were included in this retrospective analysis. Results 168 patients were divided into two groups: the group receiving adjuvant chemotherapy (AC) and the group receiving independent surgery (no-AC). Survival analysis reveals that among stage I patients, the AC group demonstrates significant superiority over the no-AC group in terms of recurrence-free survival (RFS) and overall survival (OS) (P = 0.0028; P = 0.022). While there was no discernible difference in RFS between the AC and no-AC groups for patients with stage II illness (P = 0.69), the AC group significantly outperformed the no-AC group in terms of OS (P = 0.047). There was no discernible difference in RFS or OS between the AC and no-AC groups for patients with stage III pancreatic cancer (P = 0.40 and P = 0.20, respectively). Conclusions The administration of adjuvant chemotherapy has been shown to improve the prognosis of patients diagnosed with stage I and II pancreatic cancer. However, its efficacy is limited in individuals with stage III pancreatic cancer. Therefore, there is an urgent need to investigate and develop more effective therapeutic options for patients in the advanced stage.


Introduction
Adjuvant chemotherapy ranks among the foremost measures to extend the survival of patients with pancreatic cancer following resection.Multiple large-scale randomized controlled trials have substantiated the advantageous impacts of adjuvant chemotherapy on the survival rate of pancreatic cancer patients [1][2][3].However, the potential benefits of adjuvant chemotherapy for patients with varying stages of pancreatic cancer remain unclear.A multicenter cohort study [4] has demonstrated that adjuvant chemotherapy enhances long-term survival among   patients with stage IB, IIA, IIB, and III pancreatic cancer.However, adjuvant chemotherapy does not confer a survival benefit to patients with stage IA pancreatic cancer.Furthermore, the presence of lymph node metastasis frequently correlates with a poorer prognosis in individuals with pancreatic cancer [5].The potential benefits of adjuvant chemotherapy for patients with pancreatic cancer, regardless of the presence or absence of lymph node metastasis, remain unclear.In a recent study involving 612 patients with resectable pancreatic adenocarcinoma, it was demonstrated [6] that individuals with N2 lymph node metastasis did not exhibit a response to gemcitabine-based adjuvant chemotherapy.Many pancreatic cancer patients undergo surgical resection without receiving adjuvant chemotherapy, and the reasons behind this choice may involve multiple factors.One crucial factor is the unclear value of adjuvant chemotherapy across different stages of the disease.The primary objective of this study is to evaluate the survival benefits of adjuvant chemotherapy in pancreatic cancer patients across different stages.Patients were grouped based on whether they received adjuvant chemotherapy, and independent prognostic factors were analyzed.Subsequently, survival analyses were conducted on subgroups stratified according to different stages of pancreatic cancer, aiming to identify individuals who could potentially benefit from adjuvant chemotherapy.The findings of this study may inform clinical decision-making concerning the utilization of adjuvant chemotherapy in select pancreatic cancer patients.

Data sources and patient selection
Patients with pancreatic cancer who underwent surgery at Sun Yat-sen University Cancer Center from January 2018 to January 2021 were enrolled in this retrospective study.The inclusion criteria were as follows: (1) patients with pancreatic cancer who underwent surgery and whose diagnosis was confirmed via pathological examination; (2) patients with Eastern Cooperative Oncology Group (ECOG) scores of 0-1 before surgery; (3) patients who signed the informed consent form.The exclusion criteria were as follows: (1) only abdominal exploration was performed owing to distant metastasis; (2) death within 30 days after the operation; (3) preoperative neoadjuvant therapy; (4) combined with other malignant tumors; (5) incomplete clinical characteristics or followup data.

Surgery and adjuvant chemotherapy
The surgical procedure was based on tumor location, tumor size, relationship of the tumor with surrounding important blood vessels, and regional enlarged lymph nodes, and the final decision was made by senior surgeons.R0 resection was defined as pathologically confirmed negative margins, R1 resection was defined as microscopic residual cancer, and R2 resection was defined as macroscopic residual cancer.After surgical resection, patients were evaluated for their physical condition, and adjuvant chemotherapy was initiated approximately 4 weeks after surgery.Three regimens were used for adjuvant chemotherapy: gemcitabine plus capecitabine (GP), mFOLFIRINOX, and S-1 (an oral 5-fluorouracil prodrug mixture of tegafur, gimeracil, and oteracil).In the GP regimen, gemcitabine at the dose of 1000 mg/ m 2 was intravenously infused over 30 min on days 1, 8, and 15 of each 28 day cycle for 6 cycles, and capecitabine at the dose of 1660 mg/(m 2 *d) was orally administered on days 1-21 of each 28 day cycle for 6 cycles.In Ref.
Ref. the mFOLFIRINOX regimen, oxaliplatin at the dose of 85 mg/m 2 was intravenously infused over 2 h, irinotecan at the dose of 150 mg/m 2 was intravenously infused over more than 30-90 min on day 1, L-leucovorin at the dose of 400 mg/m 2 was intravenously infused over 2 h on day 1, and 5-FU at the dose of 2400 mg/m 2 on d1, continuous intravenous infusion for 46 h, repeated every 2 weeks, was administered until 24 weeks.In the S-1 regimen, S-1 at the dose of 80 mg/d was orally administered on days 1-28 and repeated every 6 weeks until 6 months.Clinical oncologists adjusted the drug dose according to the tolerance of patients.

Follow-up and evaluation
Patients were reexamined after 1 month of surgery and subsequently every 3 months until 5 years after surgery if no recurrence was found.

Clinical characteristics of patients
A total of 168 pancreatic cancer patients were divided into two groups.Among them, 119 patients (70 males, 49 females) underwent surgery followed by adjuvant chemotherapy (AC group), while 49 patients (24 males, 25 females) underwent surgery alone (no-AC group).
After PSM implementation, a total of 96 patients were included, with 48 patients in both the no-AC and AC groups.Detailed clinical characteristics of patients are presented in Table 1.The process of inclusion, exclusion, grouping, matching, and analysis of patients with pancreatic cancer in this study is demonstrated in Fig. 1.

Survival analysis in the AC and no-AC groups
No significant difference was observed in RFS between the AC and no-AC groups (P = 0.062); however, OS was significantly better in the AC group than in the no-AC group (P = 0.029).Kaplan-Meier survival curves are demonstrated in Fig. 2.

Prognostic factors for RFS and OS analyzed via Cox regression
The results of multivariate analysis revealed that lymphatic metastasis (P = 0.001), type of surgery (P = 0.015), amount of bleeding (P = 0.011), and surgical margin (P = 0.017) were independent prognostic factors for RFS.Additionally, age (P = 0.016), pathological diagnosis (P = 0.010), and lymphatic metastasis (P = 0.047) were independent prognostic factors for OS.(Variables with P-values < 0.05 in the univariate analysis were included in the multivariate analysis.)Detailed results are presented in Table 2. Fig.

Survival analysis of patients with pancreatic cancer of different AJCC 8th edition stages
Among patients diagnosed with stage I pancreatic cancer according to the AJCC 8th edition, the AC group exhibited significantly improved RFS and OS compared to the no-AC group (P = 0.0028; P = 0.022).Among patients diagnosed with stage II pancreatic cancer, no significant difference in RFS was observed between the AC and no-AC groups (P = 0.69).However, the AC group exhibited significantly improved OS compared to the no-AC group (P = 0.047).Among patients diagnosed with stage III pancreatic cancer, no significant difference was observed in terms of RFS and OS between the AC and no-AC groups (P = 0.40; P = 0.20).Kaplan-Meier survival curves are shown in Fig. 3.

Survival analysis of patients with lymphatic metastasis
Among patients without lymph node metastasis, the AC group demonstrated significantly improved RFS and OS compared to the no-AC group (P = 0.0039; P = 0.0092).No significant disparity in RFS and OS was detected between the AC and no-AC groups among patients afflicted with lymph node metastasis (P = 0.24; P = 0.11).Kaplan-Meier survival curves are shown in Fig. 4.

Analysis of adverse events in patients who received adjuvant chemotherapy
A comprehensive evaluation of adverse effects was conducted on the cohort of 119 patients in this study.Among the cohort of 119 patients, 39 were administered GP, 29 received mFOLFIRINOX, and 51 underwent S-1 monotherapy.In the GP group, the predominant adverse reactions included nausea (48.7%), rash (46.2%), and diarrhea (43.6%).Within the mFOL-FIRINOX group, the prevailing adverse events comprised nausea (51.7%), elevated TBIL levels (48.3%), and diarrhea (44.8%).As for the S-1 group, the primary adverse reactions observed were diarrhea (49.0%), nausea (47.1%), and rash (43.1%).All patients experiencing grade 1-2 adverse reactions exhibited improvement through careful observation or symptomatic treatment.The majority of patients experiencing grade 3-4 adverse reactions exhibited improvement following drug dose reduction, withdrawal, and symptomatic treatment.Within the mFOLFIRINOX group, one patient experienced severe thrombocytopenia, which resolved after one week of drug withdrawal and platelet infusion.There were no notable disparities in the occurrence of grade 3-4 adverse reactions among the three chemotherapy groups (P > 0.05 for all), with the frequency of such reactions being less than 25.6%.
No deaths occurred as a result of adverse reactions throughout the entire study cohort.Detailed information is presented in Table 3.

Discussion
The viability and precision of the American Joint Committee on Cancer (AJCC) 8th edition staging system for pancreatic cancer have been validated through several notable large-scale studies [7,8].Moreover, adjuvant chemotherapy has been demonstrated to significantly prolong the survival time of pancreatic cancer patients.
The CONKO-001 study, a captivating multicenter, randomized controlled phase III clinical trial encompassing 368 patients [1], demonstrated that patients who received surgery combined with gemcitabine-based adjuvant chemotherapy experienced a remarkable extension in disease-free survival (DFS) and OS compared to those who underwent surgery alone.Notably, the median DFS reached an impressive 13.4 months compared to 6.7 months (P < 0.001).Subsequent studies [2,3,9] proposed alternative approaches apart from using gemcitabine as a standalone treatment.However, the benefits of adjuvant chemotherapy over surgery alone for pancreatic cancer patients stratified by AJCC staging remain uncertain.Further research is still needed to explore the relationship between the efficacy of adjuvant chemotherapy and AJCC staging in pancreatic cancer.Gervaso et al. [10] emphasized in a comprehensive review that the decision regarding adjuvant therapy in stage I pancreatic cancer patients remains a challenge, necessitating further data to draw definitive conclusions.
The findings of this study may potentially address this crucial issue.This study unveiled that in stage I pancreatic cancer patients, the AC group demonstrated significantly enhanced RFS and OS in comparison to the no-AC group (P = 0.0028; P = 0.022).Similarly, Turner et al. [11] demonstrated that patients diagnosed with stage IA pancreatic cancer who received adjuvant chemotherapy experienced a significantly prolonged median OS of 105.7 months, surpassing those who underwent surgery alone (72.0 months) (P < 0.01).Furthermore, Guenther et al. [12] observed analogous findings in a cohort of 124 patients with stage I pancreatic cancer.Interestingly, Izumo et al. [13] reported seemingly disparate findings.They stratified stage IA pancreatic cancer patients into low-risk and high-risk groups based on clinical and pathological factors, revealing that adjuvant chemotherapy exhibited greater efficacy in the highrisk group.Moreover, it is imperative to acknowledge that the duration of this study, spanning from 2018 to 2021, was comparatively shorter than that of other studies, effectively mitigating the heterogeneity of treatment regimens.These results illustrate that the benefit of postoperative adjuvant chemotherapy varies according to AJCC stage, and the standard chemotherapy regimen should be questioned whether it is appropriate for each patients.For patients with stage I and II pancreatic cancer, current standard adjuvant chemotherapy regimens are relatively effective.However, the survival of patients with stage III pancreatic cancer from current postoperative chemotherapy is relatively modest, suggesting that more aggressive chemotherapy regimens may be needed or that clinical trials will be conducted to identify more effective regimens.
Considering the inherent biases associated with retrospective, single-center data, we endeavored to mitigate this limitation by employing a PSM approach.PSM is a statistical methodology employed in observational studies, alleviating the impact of selection bias and confounding variables, thereby rendering the comparison between the experimental and control groups more robust [14,15].Nevertheless, it is crucial to acknowledge several limitations of this study.Firstly, we did not explore the impact of retreatment after cancer recurrence on OS.Secondly, the prognostic significance of histological differentiation in pancreatic cancer has been widely recognized; however, we did not stratify and analyze survival based on this factor.Lastly, the sample size was limited, and all participants were from southern China, potentially compromising the generalizability of the study population.The conclusions of this study need to be verified by external data from different populations and regions, and only in this way can the conclusions of this study be convincing enough.
In conclusion, our study findings indicate the beneficial effects of adjuvant chemotherapy on both RFS and OS in stage I pancreatic cancer patients.For stage II pancreatic cancer, adjuvant chemotherapy improves OS but does not affect RFS.However, in stage III pancreatic cancer, adjuvant chemotherapy fails to improve both RFS and OS.Therefore, further clinical research is warranted to establish effective adjuvant chemotherapy regimens specifically tailored for stage III pancreatic cancer patients.
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Fig. 1
Fig. 1 Flow chart of the patient enrolling process

Fig. 2 2
Fig. 2 Kaplan-Meier analyses for RFS and OS based on adjuvant chemotherapy.A, RFS in the AC group versus the no-AC group; B, OS in the AC group versus the no-AC group

Fig. 4
Fig. 4 Kaplan-Meier analyses for RFS and OS based on adjuvant chemotherapy.A, RFS in the AC group versus the no-AC group in patients without lymph node metastasis; B, OS in the AC group versus the no-AC group in patients without lymph node metastasis; C, RFS in the AC group versus the no-AC group in patients with lymph node metastasis; D, OS in the AC group versus the no-AC group in patients with lymph node metastasis

Table 1
Baseline clinicopathological characteristics based on Adjuvant chemotherapy, before and after propensity score matching

Propensity score matching and statistical analysis
The reexamination encompassed blood routine tests, liver and kidney function assessments, pancreatic tumor marker evaluations, as well as upper abdominal computed tomography (CT) and magnetic resonance imaging (MRI) scans (plain scan + enhanced).The follow-up period extended until January 1, 2023, serving as the cutoff date.Adjuvant chemotherapy's efficacy was assessed based on overall survival (OS) and recurrence-free survival (RFS).RFS was defined as the time from surgery to the first recording of tumor recurrence or metastasis.OS was defined as the time from surgery to death from any cause or to the last follow-up.Major adverse events were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.

Table 3
Postoperative adjuvant chemotherapy related adverse reactions